Peptide analogs of bombesin

Abstract

Linear peptide analogs of bombesin with modified amino acid residues at various positions. A peptide of a group of bombesin analogs according to this invention contains either a --CH 2 NH 2 -- pseudopeptide bond, a (3S,4S)-4-amino-3-hydroxy- 6-methylheptanoic acid residue, or a (3S,4S)-4-amino-3- hydroxy-5-phenylpentanoic acid residue.

What is claimed is: 
     
       1. A peptide of the formula: ##STR2## wherein A 1  is D- or L- isomer of pGlu, or deleted; A 2  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, β-Nal, or deleted;   A 3  is the D- or L- isomer selected from Arg and Lys, or deleted;   A 4  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, β-Nal, or deleted;   A 5  is Gly, the D- or L- isomer selected from Gln, Asn, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which x is F, Cl, Br, OH, or CH 3 , Trp and β-Nal, or deleted;   A 6  is Gly, the D- or L- isomer selected from Gln, Asn, Ala, N--Ac-D-Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, and β-Nal, or deleted;   A 7  is Gly, or the D- or L- isomer selected from Gln, Asn, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, Lys, His, and β-Nal;   A 8  is Trp or Met;   A 9  is Sta, AHPPA, Gly, or the D- or L- isomer selected from Gln, Asn, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, and β-Nal;   A 10  is Sta, AHPPA, Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, Thr, or β-Nal;   A 11  is Sta, AHPPA, Gly, or the D- or L- isomer selected from Ala, and Phe;   A 12  is Sta, AHPPA, or the D- or L- isomer selected from His, Phe, and p-X-Phe in which X is F, Cl, Br, OH, or CH 3  ;   A 13  is Sta, AHPPA, Gly, or the D- or L- isomer selected from Gln, Asn, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, and β-Nal;   A 14  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, or β-Nal;   each of R 1  and R 2 , independently, is H, Phenylalkyl, CO.E 1  in which E 1  is C 1-20  alkyl, C 2-20  alkynyl, Phenyl, naphthyl or C 7-10  Phenylalkyl, or CO.OE 2  in which E 2  is C 1-10  alkyl or C 7-10  Phenylalkyl; and   each of R 3  and R 4 , independently, is H, C 1-12  alkyl, C 7-10  Phenylalkyl;   provided that when one of R 1  and R 2  is CO.E 1  or CO.OE 2 , the other must be H; further provided that when A 1  is Pglu, one of R 1  and R 2  must be H and the other must be the portion of Pglu that forms the imine ring, and when the N-terminal amino acid is Saa, one of R 1  and R 2  must be the N.sup.α -substitutent of said Saa; provided that either the carbon atom participating in the amide bond between one and only one pair of neighboring amino acids selected from A 7  and A 8 , A 8  and A 9 , A 9  and A 10 , A 11  and A 12 , A 12  and A 13 , and A 13  and A 14  is a methylene carbon, or one and only one of A 9 , A 10 , A 11 , A 12 , and A 13  is Sta or AHPPA; and further provided that the next higher numbered amino acid residue adjacent to Sta or AHPPA must be deleted; or a pharmaceutically acceptable salt thereof.   
     
     
       2. The peptide of claim 1, wherein: A 1  is pGlu, or deleted;   A 2  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, β-Nal, or deleted;   A 3  is the D- or L- isomer selected from Arg and Lys, or deleted;   A 4  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, β-Nal, or deleted;   A 5  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, D-Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, β-Nal, D-Ala, or deleted;   A 6  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, β-Nal, or deleted;   A 7  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, D-Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, or β-Nal;   A 8  is Trp;   A 9  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, or β-Nal;   A 10  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, or β-Nal;   A 11  Gly or D-Ala;   A 12  is His, Phe, or p-X-Phe in which X is F, Cl, Br, OH, or CH3;   A 13  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, or β-Nal; and   A 14  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, or β-Nal; or a pharmaceutically acceptable salt thereof.   
     
     
       3. The peptide of claim 1, wherein one of R 1  and R 2  is Phenylpropionyl and the other is H; or a pharmaceutically acceptable salt thereof. 
     
     
       4. The peptide of claim 1, wherein A 1  through A 5  are deleted and the carbon atom participating in the amide bond between A 13  and A 14  is a methylene carbon; or a pharmaceutically acceptable salt thereof. 
     
     
       5. The peptide of claim 1, wherein each of A 13  and A 14  independently is Phe or Leu; or a pharmaceutically acceptable salt thereof. 
     
     
       6. The peptide of claim 1, wherein the carbon atom participating in the amide bond between A 11  and A 12 , A 12  and A 13 , or A 13  and A 14  is a methylene carbon; or a pharmaceutically acceptable salt thereof. 
     
     
       7. The peptide of claim 1, wherein A 9  is Gly, or the D- or L- isomer selected from Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, and β-Nal;   A 10  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, Thr, or β-Nal;   A 11  is Gly, or the D- or L- isomer selected from Ala, Eaa, and Phe;   A 12  is D- or L- isomer selected from His, Phe, and p-X-Phe in which X is F, Cl, Br, OH, or CH 3  ; and   A 13  is Gly, or the D- or L- isomer selected from Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, Tic, Tip, Oic, Tcc, and β-Nal; or a pharmaceutically acceptable salt thereof.   
     
     
       8. The peptide of claim 1, wherein one and only one of A 9 , A 10 , A 11 , A 12  and A 13  is Sta or AHPPA; or a pharmaceutically acceptable salt thereof. 
     
     
       9. The peptide of claim 1, said peptide having the formula: pGlu-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Ψ-Gly-His-Leu-Leu-NH 2;   or a pharmaceutically acceptable salt thereof.     
     
     
       10. The peptide of claim 1, said peptide having the formula: pGlu-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Sta-NH 2  ; or a pharmaceutically acceptable salt thereof.     
     
     
       11. A peptide of the formula: ##STR3## wherein A 1  is D- or L- isomer of pGlu, or deleted; A 2  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, βNal, or deleted;   A 3  is the D- or L- isomer selected from Arg and Lys, or deleted;   A 4  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, βNal, or deleted;   A 5  is Gly, the D- or L- isomer selected from Gln, Asn, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, D-Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp and β-Nal, or deleted;   A 6  is Gly, the D- or L- isomer selected from Gln, Asn, Ala, N--Ac-D-Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl,, Br, OH, or CH 3 , pentafluoro-Phe, Trp, and β-Nal, or deleted;   A 7  is Saa;   A 8  is Trp or Met;   A 9  is Sta, AHPPA, Gly, or the D- or L- isomer selected from Gln, Asn, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, and βNal;   A 10  is Sta, AHPPA, Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, Thr, or β-Nal;   A 11  is Sta, AHPPA, Gly, or the D- or L- isomer selected from Ala, Eaa, and Phe;   A 12  is Sta, AHPPA, or the D- or L- isomer selected from His, Phe, and p-X-Phe in which X is F, Cl, Br, OH, or CH 3  ;   A 13  is Sta, AHPPPA, Gly or the D- or L- isomer selected from Gln, Asn, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, Pro, Tic, Tip, Oic, Tcc, and β-Nal;   A 14  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, Tic, Tip, Oic, Tcc, or β-Nal;   each of R 1  and R 2 , independently, is H, C 1-12  alkyl, C 7-10  Phenylalkyl, CO.E 1  in which E 1  is C 1-20  alkyl, C 2-20  alkenyl, C 2-20  alkynyl, Phenyl, naphthyl, or C 7-10  Phenylalkyl, or CO.OE 2  in which E 2  is C 1-10  alkyl or C 7-10  Phenylalkyl; and   each of R 3  and R 4 , independently, is H, C 1-12  alkyl, or C 7-10  Phenylalkyl;   provided that when one of R 1  and R 2  is CO.E 1  or CO.OE 2 , the other must be H; further provided that when A 1  is pGlu, one of R 1  and R 2  must be H and the other must be the portion of pGlu that forms the imine ring, and when the N-terminal amino acid is Saa, one of R 1  and R 2  must be the Nα-substitutent of said Saa; provided that either the carbon atom participating in the amide bond between one and only one pair of neighboring amino acids selected from A 7  and A 8 , A 8  and A 9 , A 9  and A 10 , A 11  and A 12 , A 12  and A 13 , and A 13  and A 14  is a methylene carbon, or one and only one of A 9 , A 10 , A 11 , A 12 , and A 13  is Sta or AHPPA; and further provided that the next higher numbered amino acid residue adjacent to Sta or AHPPA must be deleted; or a pharmaceutically acceptable salt thereof.   
     
     
       12. The peptide of claim 11, wherein A 9  is Gly, or the D- or L- isomer selected from Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, and β-Nal;   A 10  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, Thr, or β-Nal;   A 11  is Gly, or the D- or L- isomer selected from Ala, Eaa, and Phe;   A 12  is the D- or L- isomer selected from His, Phe, and p-X-Phe in which X is F, Cl, Br, OH, or CH 3  ; and   A 13  is Gly, or the D- or L- isomer selected from Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, Pro, Tic, Tip, Oic, Tcc, and β-Nal; or a pharmaceutically acceptable salt thereof.   
     
     
       13. The peptide of claim 12, wherein A 7  is Sar, or the D- or L- isomer selected from Pro, homo-Pro, N-me-Ala, Tic, Tip, Tcc, and Oic; or a pharmaceutically acceptable salt thereof. 
     
     
       14. The peptide of claim 12, wherein A 11  is Eaa. 
     
     
       15. The peptide of claim 11, wherein one and only one of A 9 , A 10 , A 11 , A 12  and A 13  is Sta or AHPPA; or a pharmaceutically acceptable salt thereof. 
     
     
       16. A peptide of the formula: ##STR4## wherein A 1  is the D- or L- isomer of pGlu, or deleted; A 2  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, β-Nal, or deleted;   A 3  is the D- or L- isomer selected from Arg and Lys, or deleted;   A 4  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, β-Nal, or deleted;   A 5  is Gly, the D- or L- isomer selected from Gln, Asn, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, D-Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp and β-Nal, or deleted;   A 6  is Gly, the D- or L- isomer selected from Gln, Asn, Ala, N--Ac-D-Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , pentafluoro-Phe, Trp, and β-Nal, or deleted;   A 7  is Gly, or the D- or L- isomer selected from Gln, Asn, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, D-Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, Lys, His, Saa, and β-Nal;   A 8  is Trp or Met;   A 9  is Sta, AHPPA, Gly, or the D- or L- isomer selected from Gln, Asn, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, and β-Nal;   A 10  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, Thr, or β-Nal;   A 11  is or Eaa;   A 12  is Sta, AHPPA, the D- or L- isomer selected from His, Phe, and p-X-Phe in which X is F, Cl, Br, OH, or CH 3  ;   A 13  is Sta, AHPPA, Gly, or the D- or L- isomer selected from Gln, Asn, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, Pro, Tic, Tip, Oic, Tcc, and β-Nal;   A 14  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, Tic, Tip, Oic, Tcc, or β-Nal;   each of R 1  and R 2 , independently, is H, C 1-12  alkyl, C 7-10  Phenylalkyl, CO.E 1  in which E 1  is C 1-20  alkyl, C 2-20  alkenyl, C 2-20  alkynyl, Phenyl, naphthyl, or C 7-10  Phenylalkyl, or CO.OE 2  in which E 2  is C 1-10  alkyl or C 7-10  Phenylalkyl; and   each of R 3  and R 4 , independently, is H, C 1-12  alkyl, or C 7-10  Phenylalkyl;   provided that when one of R 1  and R 2  is CO.E 1  or CO.OE 2 , the other must be H; further provided that when A 1  is pGlu, one of R 1  and R 2  must be H and the other must be the portion of pGlu that forms the imine ring, and when the N-terminal amino acid is Saa, one of R 1  and R 2  must be the N.sup.α -substitutent of said Saa; provided that either the carbon atom participating in the amide bond between one and only one pair of neighboring amino acids selected from A 7  and A 8 , A 8  and A 9 , A 9  and A 10 , A 11  and A 12 , A 12  and A 13 , and A 13  and A 14  is a methylene carbon, or one and only one of A 9 , A 10 , A 11 , A 12 , and A 13  is Sta or AHPPA; and further provided that the next higher numbered amino acid residue adjacent to Sta or AHPPA must be deleted; or a pharmaceutically acceptable salt thereof.   
     
     
       17. The peptide of claim 16, wherein A 9  is Gly, or the D- or L- isomer selected from Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, and β-Nal;   A 10  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, Thr, or β-Nal;   A 11  is Eaa;   A 12  is the D- or L- isomer selected from His, Phe, and p-X-Phe in which X is F, Cl, Br, OH, or CH 3  ; and   A 13  is Gly, or the D- or L- isomer selected from Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, Pro, Tic, Tip, Oic, Tcc, and β-Nal; or a pharmaceutically acceptable salt thereof.   
     
     
       18. The peptide of claim 17, wherein A 11  β-Ala, γ-aminobytyric acid, or 5-aminopentanoic acid; or a pharmaceutically acceptable salt thereof. 
     
     
       19. The peptide of claim 16, wherein one and only one of A 9 , A 12 , and A 13  is Sta or AHPPA; or a pharmaceutically acceptable salt thereof. 
     
     
       20. A peptide of the formula: ##STR5## wherein A 5  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, D-Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, β-Nal, or deleted; A 6  is Gln, Asn, Gly, Ala, D-Ala, N-Ac-D-Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, p-Glu, Trp, β-Nal, or deleted;   A 7  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, D-Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, Lys, His, or β-Nal;   A 8  is Trp or Met;   A 9  is the D- or L-isomer selected from Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, and β-Nal;   A 10  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, Thr, or β-Nal;   A 11  is Gly, or the D- or L- isomer selected from Ala and Phe;   A 12  is the D- or L- isomer selected from His, Phe, and p-X-Phe in which X is F, Cl, Br, OH, or CH 3  ;   A 13  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, or β-Nal;   A 14  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, or β-Nal;   each of R 1  and R 2 , independently, is H, C 1-12  alkyl, C 7-10  Phenylalkyl, CO.E 1  in which E 1  is C 1-20  alkyl, C 2-20  alkenyl, C 2-20  alkynyl, Phenyl, naphthyl, or C 7-10  Phenylalkyl, or CO.OE 2  in which E 2  is C 1-10  alkyl or C 7-10  Phenylalkyl; and   each of R 3  and R 4 , independently, is H, C 1-12  alkyl, or C 7-10  Phenylalkyl;   provided that when one of R 1  and R 2  is CO.E 1  or CO.OE 2 , the other must be H; further provided that when A 1  is pGlu, one of R 1  and R 2  must be H and the other must be the portion of pGlu that forms the imine ring, and when the N-terminal amino acid is Saa, one of R 1  and R 2  must be the N.sup.α -substitutent of said Saa; and further provided that the carbon atom participating in the amide bond between A 13  and A 14  is either a carbonyl carbon or a methylene carbon; or a pharmaceutically acceptable salt thereof.   
     
     
       21. The peptide of claim 20, wherein A 5  is deleted;   A 6  is Gln, Asn, Gly, Ala, D-Ala, N--Ac-D-Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, p-Glu, Trp, β-Nal, or deleted;   A 7  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, D-Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, Lys, His, or β-Nal;   A 8  is Trp or Met;   A 9  is the D- or L-isomer selected from Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, and β-Nal;   A 10  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, Thr, or β-Nal;   A 11  is Gly, or the D- or L- isomer selected from Ala and Phe;   A 12  is the D- or L- isomer selected from His, Phe, and p-X-Phe in which X is F, Cl, Br, OH, or CH 3  ;   A 13  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, or β-Nal; and   A 14  is Gln, Asn, Gly, Ala, Leu, Ile, Nle, Abu, Met, Val, Phe, p-X-Phe in which X is F, Cl, Br, OH, or CH 3 , Trp, or β-Nal; or a pharmaceutical salt thereof.